Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma

Roshan Mahabir, Mishie Tanino, Aiman Elmansuri, Lei Wang, Taichi Kimura, Tamio Itoh, Yusuke Ohba, Hiroshi Nishihara, Hiroki Shirato, Masumi Tsuda, Shinya Tanaka

研究成果: Article査読

103 被引用数 (Scopus)

抄録

BackgroundIonizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown.MethodsTo investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines.ResultsIn 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3β were increased after irradiation in a Snail-dependent manner, and TGF-β was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo.ConclusionsWe here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

本文言語English
ページ(範囲)671-685
ページ数15
ジャーナルNeuro-oncology
16
5
DOI
出版ステータスPublished - 2014 5
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 臨床神経学
  • 癌研究

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